The purpose of this proposal is to investigate the pathophysiology of human B cell maturation by relating a series of events intervening between the initial activation signal and Ig secretion to: a) the intrinsic B cell defects of patients with acquired hypogammaglobulinemia (AH); and b) regulatory influences from T helper or suppressor cells and macrophages. Early activation events to be compared in normal and defective B cell responding to mitogen include (in approximate order of occurrence): anti-Ig inducing capping, accelerated lipid synthesis, protein phosphorylation, 28S/18S ribosomal RNA ratio, surface Ig replacement, T helper factor absorption, surface IgD loss and IgG gain, and proliferation. After the non-T suppressor present in 4/9 of our patients is shown to be a macrophage, the early events affected and not affected by AH suppressor macrophges, AH and normal T suppressors and normal T help will be determined to provide insights into the interaction of immunoregulatory signals with normal B cell maturation and the defects preventing B cell maturation in AH. The long range purpose of acquiring this knowledge is to learn how to devise new therapeutic approaches to the pathophysiology of individual patients by appropriate modulation of the immunoregulatory circuits.